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This study established an experimental model of replicative Legionella longbeachae infection in A/J mice. The animals were infected by intratracheal inoculation of 103–109 c.f.u. L. longbeachae serogroup 1 (USA clinical isolates D4968, D4969 and D4973). The inocula of 109, 108, 107 and 106 c.f.u. of all tested L. longbeachae serogroup 1 isolates were lethal for A/J mice. Inoculation of 105 c.f.u. L. longbeachae caused death in 90 % of the animals within 5 days, whilst inoculation of 104 c.f.u. caused sporadic death of mice. All animals that received 103 c.f.u. bacteria developed acute lower respiratory disease, but were able to clear Legionella from the lungs within 3 weeks. The kinetics of bacterial growth in the lungs was independent of inoculum size and reached a growth peak about 3 logarithms above the initial inoculum at 72 h after inoculation. The most prominent histological changes in the lungs were observed at 48–72 h after inoculation in the form of a focal, neutrophil-dominant, peribronchiolar infiltration. The inflammatory process did not progress towards the interstitial or alveolar spaces. Immunohistological analyses revealed L. longbeachae serogroup 1 during the early phase of infection near the bronchiolar epithelia and later co-localized with inflammatory cells. BALB/c and C57BL/6 mice strains were also susceptible to infection with all L. longbeachae serogroup 1 strains tested and very similar changes were observed in the lungs of infected animals. These results underline the infection potential of L. longbeachae serogroup 1, which is associated with high morbidity and lethality in mice.

Carvacrol has been shown to possess anticancer activity, but the mechanism is unknown, as well as the possibility of interaction with anticancer drugs. The aim of this study was to investigate the role of mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling in carvacrol-induced human cervical cancer HeLa cell cytotoxicity. In addition, we studied sensitization of HeLa cells to cisplatin (CP) by carvacrol. Both carvacrol and CP showed dose-dependent cytotoxicity against HeLa cells and activated ERK1/2. The MEK inhibitor PD325901 suppressed ERK expression and further increased cytotoxicity of carvacrol but increased viability of CP-treated cells by modulating apoptosis. The MEK inhibitor also increased microtubule-associated protein 1A/1B-light chain 3 beta expression in CP treatment. Cotreatment with CP and carvacrol resulted in increased viability of the cancer cells compared with CP treatment, which was associated with the suppression of apoptosis. MEK inhibition decreased the cell viability, without changes in apoptosis. Concomitantly, carvacrol increased CP-induced expression of light chain 3 beta, which was enhanced by MEK inhibition. The results of the current study suggest the opposite role of ERK1/2 in carvacrol and CP-induced HeLa cell cytotoxicity. Interestingly, carvacrol induced CP resistance in HeLa cells through ERK1/2-independent suppression of apoptosis and ERK1/2-dependent modulation of autophagy.

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